Lack of effectiveness of Bebtelovimab monoclonal antibody among high-risk patients with SARS-Cov-2 Omicron during BA.2, BA.2.12.1 and BA.5 subvariants dominated era

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N = 1,091) compared to propensity score (PS) matched control (N = 1,091). The primary composite outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary composite outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p = 0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or ≥65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026–0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.


Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported (Intro) describes lack of Phase III trials and real world experiences regarding effectiveness of Beblovimab (BEB) in era of SARS-CoV-2 Omicron subvariants. Objectives 3 State specific objectives, including any prespecified hypotheses (Intro) "Comparison of all-cause hospitalization and/or death over 30-day in high-risk outpatients, who received BEB MAb compared to the propensity score (PS) matched untreated control group for COVID-19 dominated by SARS-CoV-2 Omicron BA.2, BA.2.12.1, and BA.5 subvariants"

Study design 4
Present key elements of study design early in the paper 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm Describe any efforts to address potential sources of bias Cohort study, as described in Methods, Flow Chart (Figure 1), and follow-up summary (Table 1).
All-cause hospitalization and death within 30 days of index date, as detailed in methods. The exposure variable (BEB MAb use) clearly called out. The BEB MAb and control group were propensity matched based on 26 variables in the EHR, explained in Methods, the covariant balance pre and post-PS match was assessed ( Table  1). The study conserved sample size/power for main effect estimation; effect modification was not performed.
Clinical covariates were derived from the Charlson Comorbidity Index codes (based on International Classification of Diseases, Tenth Revision [ICD-10] codes) documented in the Cerner-EHR within five years preceding the index date.
To reduce selection bias associated with the decision to administer BEB MAb, we utilized a 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function.

(b) Describe any methods used to examine subgroups and interactions
We also fitted a multivariable Cox proportional hazard regression model predicting the composite outcome in the PS matched subgroups. The Kaplan-Meier estimator was used to plot curves for the composite outcome between the post-PS matched groups. (c) Explain how missing data were addressed The vaccination status was missing for 4.1% of the patients for both groups in the post-propensity matched cohort (Table 1).
Missing vaccination status was analyzed as a separate category (fully vaccinated, not fully vaccinated, unknown (missing).

(d) Cohort study-If applicable, explain how loss to follow-up was addressed
We assumed that all patients in the study cohort were followed in the Banner Healthcare system and followup was complete. We stated the possibility of primary outcome out-of-Banner system hospitalization as a limitation in the Discussion section.

Case-control study-If applicable, explain how matching of cases and controls was addressed
Cross-sectional study-If applicable, describe analytical methods taking account of sampling strategy  Table 1 (c) Cohort study-Summarise follow-up time (eg, average and total amount) Included in Table 1. Each patient had at least 30 days follow-up postindex date.
Outcome data 15* Cohort study-Report numbers of outcome events or summary measures over time Included in Table 2 and Table3.
Case-control study-Report numbers in each exposure category, or summary measures of exposure

N/A
Cross-sectional study-Report numbers of outcome events or summary measures

N/A
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included Comparative proportions along with confidence intervals in the post-propensity score matched cohort and their re-matched subgroups in Table  2-3.

Other analyses 17
Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses Subgroup analysis for vaccinated status, age (65 or below and >65), immunosuppressed status were described and shown in Table 3. Sensitivity analysis was not performed and interaction effects were not tested.

Key results 18
Summarise key results with reference to study objectives Description of results aligns with stated objective of estimating independent effects of the BEB MAb use.
Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias Limitations, including retrospective study design, unmeasured confounding, prior COVID -19 exposures, lack of viral genotyping, and others are discussed extensively in the Discussion section.

Interpretation 20
Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence